Intervertebral disc degeneration (IDD) is typically accompanied by a reduced nutrient supply, which is thought to be a contributor to the apoptosis of nucleus pulposus cells (NPCs). Here, we explored whether Forkhead box O3 (FOXO3), a key transcription factor involved in cellular quality control, could protect NPCs against apoptosis under nutrient deficiency. Firstly, we found that FOXO3 knockdown aggravated nutrient deficiency-induced mitochondrial dysfunction, apoptosis and matrix degradation in NPCs. In addition, the siRNA-mediated downregulation of FOXO3 suppressed mitophagy in starved NPCs. However, when we overexpressed FOXO3 in NPCs by lentivirus transfection, the observed detrimental effects induced by nutrient deprivation were significantly reversed by the FOXO3-activated autophagy. Moreover, by analyzing the human NP samples from different age groups as well as degenerated groups, we found that the FOXO3 protein level decreased with aging and degeneration. Together, our data suggest that FOXO3 plays a vital role in disc degeneration and can be a novel therapeutic target for IDD. (C) 2020 Elsevier Inc. All rights reserved.